Method for control of temperature-sensitivity of polymers in solution

ABSTRACT

Temperature sensitive, water soluble polymers are disclosed, together with a method for control the LCST of the polymer. The polymers include hydrophillic components and hydrophobic components joined by linking groups such as ester or amide groups wherein the hydrophilic components includes m ethylene oxide groups, the hydrophobic components consist of aliphatic groups such as n ethylenes and/or n cycloaliphatic groups, and where 1≦m≦30 and 1≦n≦30. Substrates bearing the grafted temperature responsive polymers also are disclosed. Microfluidic devices which include the temperature responsive polymers also are disclosed.

This application is a CON of Ser. No. 10/389,672 filed Mar. 14, 2003,which claims priority to U.S. Provisional Application U.S. Ser. No.60/365,468 filed Mar. 15, 2002.

BACKGROUND OF THE INVENTION

Many polymer solutions exhibit phase separation phenomena, which occurat specific temperatures characteristic of the concentration and thesystem (usually referred to as binodal temperatures or as cloud points).Above or below the cloud point temperature, the polymer is soluble andthe solution is clear, but below or above this temperature, the polymerbecomes insoluble and phase separates and the solution becomes opaque.In most polymer-solvent systems solubility decreases with fallingtemperature, but in some cases involving polar polymers, the oppositeoccurs and the polymer suddenly phase separate at a specific, highertemperature; the cloud-point temperature is in such cases a lowercritical solution temperature (LCST). Polymer solutions in which thecloud point temperature occurs at low critical solution temperatureshave been described in Japanese patent Nos. 85 190444; 85 208336; and 8666707. These aqueous solutions include gels of poly-isopropylacrylamideand of isopropyl acrylamide/N-methylolacrylamide copolymers and ofpyrrolidyl or piperidyl/acrylamide copolymers. Besides theseacrylamides; N-iso-, N-n-, N-cyclopropylacrylamide and the correspondingmethacrylamides are described in these patents, as well asN,N-diethylacrylamide as the only disubstituted acrylamide.

Thermally-sensitive polymers having an LCST in aqueous solution are wellknown in the art. See, e.g., Hoffman, A. “Intelligent Polymers” in Park,K, ed., Controlled Drug Delivery: Challenges and Strategies, AmericanChemical Soc., Washington, D.C. (1997). These polymers show fairly largephysical changes (or transitions) in response to temperature, and haveas a common property a balance of hydrophilic and hydrophobic groups. Athermally induced phase separation causes the release of hydrophobicallybound water, and a resulting change in the conformation and propertiesof the polymer. The combination of a thermally sensitive polymer with apH sensitive component can make the thermally-sensitive polymersensitive to pH changes because the ionization, and thus hydrophilicity,of the pH-sensitive component can be changed by changing the pH.

Water soluble polymers with thermal sensitivity are of great scientificand technological importance. Such “smart” or “responsive” polymers arestarting to find applications in pharmaceutical, biotechnological,chemical, and other such industries. For nonionic polymers, in mostcases the thermosensitive character originates from the existence of alower critical solution temperature (“LCST”), beyond which the polymerbecomes insoluble in water.

Driven by the high promise for biomedical applications, polymers thatexhibit a response in water at about 37° C. are of particular interest.The most commonly studied homopolymer (poly(N-isopropylacrylamide).PNIPAM), with a transition in water at 32° C. is not approved for humanuse. Furthermore, efforts to tailor the LCST of acrylamides to atemperature different than 32° C. by means of attaching hydrophobic orhydrophilic branches to these polymers, resulted in very broadtransitions, that take place over tens of degrees centigrade, and do notcorrespond to the hydrophilic/hydrophobic balance. See, e.g. Laschewskyet al. “Tailoring of Stimuli-Responsive Water Soluable Acrylamide andMethacrylamide Polymers” Macromolec. Chem. Phys. 2001, vol 202, pg.276-286. On the other hand, polyethylene oxide (PEO). which is currentlyused in many biomedical devices, has a LCST in water at about 150° C.rendering it of limited use for biomedical applications which require atemperature response.

A need therefore exists for polymers which show sharp transitiontemperature behavior in solution at lower temperatures. A further needexists for methods of manufacture of these polymers as well as methodsfor control of the transition behavior of the polymers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the sharp phase transition behavior of various polymers ofthe invention such as selected polyesters and polyamides of the formulae(1),(2),(3), and (4) with varied m/n ratios, i.e.ethylene-oxide/ethylene ratios.

SUMMARY OF THE INVENTION

The present invention relates to water-soluble polymers containing bothhydrophilic groups and hydrophobic groups. The LCST of the polymers inaqueous solution may be controlled by varying the fractions of thehydrophilic groups and hydrophobic groups, while maintaining certainpolymer microstructures.

The present invention relates to temperature responsive polymers, and tocontrol of the temperature-response of the polymers in aqueoussolutions. The polymers represent a new class of temperature sensitivepolymers which have controllable phase transition temperatures in water,and have applicability to drug delivery in response to temperaturestimuli, cell adhesion control such as in substrates modified by thesepolymers, and microflow control such as in microfluidic devices.

In a first aspect, linear polymers such as linear polyesters weresynthesized from monomers which include hydrophilic ethylene-oxide unitsand hydrophobic ethylene units. By control of the fractions of thehydrophilic monomer and hydrophobic monomer in the polymer, the LCST ofthe polymer in solution may be controlled over a wide temperature range.

In another aspect, the invention relates to temperature sensitive,aqueous polymer compositions. The compositions include linear copolymersthat has a lower critical solution temperature of about 7° C. to about70° C. The copolymers include hydrophilic components and hydrophobiccomponents. Preferably, the hydrophilic component includes (ethyleneoxide) groups and the hydrophobic component is an aliphatic chainincludes ethylene groups. The phase separation temperature of theaqueous solution can be controlled by varying the relative lengths ofthe hydrophilic and the hydrophobic components in an alternating orrandom copolymer microstructure.

Advantageously, the invention achieves Thermosensitive, water solublepolymers which exhibit a typical polymer-solvent phase behavior. Inaddition, the invention achieves a method for control of the temperatureresponse of the polymers by varying the molar fractions of amounts ofhydrophobic components(n) and hydrophilic components(m).

In a preferred aspect, the invention relates to a temperature sensitive,water soluble polymer of formula (1)

that includes a hydrophilic component and a hydrophobic component joinedby a linking group wherein the hydrophilic component includes m(ethylene oxide) groups, the hydrophobic component includes n ethylenegroups, and the linking group is an ester, and where 1≦m≦30 and 1≦n≦30.More preferably in the polymer of formula 1, m=4 and n=3; m=5 and n=3;m=13 and n=3; m=5 and n=5; and m=13 and n=5.

In another preferred aspect, the invention relates to a temperaturesensitive, water soluble polyester of formula (2)

that includes a hydrophilic component and a hydrophobic component joinedby a linking group wherein the hydrophilic component includes m(ethylene oxide) groups, the hydrophobic component includes n ethylenegroups and the linking group is an methylene-ester group, where 1≦m≦30ethylene oxide and 1≦n≦30 ethylene. More preferably, in the polymer offormula (2), m=5 and n=6; m=13 and n=6; m=5 and n=3; and m=13 and n=3.

In yet another preferred aspect, the invention relates to a temperaturesensitive, water soluble polyamide of formula (3)

that includes a hydrophilic component and a hydrophobic component joinedby a linking group wherein the hydrophilic component includes m(ethylene oxide) groups, the hydrophobic component includes n ethylenegroups, and the linking group is an amide group, where 1≦m≦40 ethyleneoxide and 1≦n≦30 ethylene. More preferably, m=5 and n=5; m=13 and n=5;m=13 and n=3.

In a further preferred aspect, the invention relates to a temperaturesensitive, water soluble polyamide of formula (4)

that includes a hydrophilic component and a hydrophobic component joinedby a linking group wherein the hydrophilic component includes m(ethylene oxide) groups, the hydrophobic group ismethylene-biscyclohexanamine and the linking group is an amide, where1≦m≦40 ethylene oxide. More preferably, m=5; m=13.

The invention also relates to substrates which bear a graftedtemperature responsive polymer. In this aspect, the invention relates toa substrate material having a self assembled monolayer thereon, and atemperature responsive polymer of any of formulae (1) to (4):

where 1≦m≦30 and 1≦n≦30,

where 1≦m≦30 ethylene oxide and 1≦n≦30 ethylene,

where 1≦m≦40 ethylene oxide and 1≦n≦30 ethylene, and

where 1≦m≦40 ethylene oxide.

Preferably, the substrate material is any of metal, metal oxide,ceramic, semiconductor, polymer, glass and silicon, and a mixed selfassembled monolayer. The mixed monolayer includes methyl terminatedmolecules such as alkyl-silanes, preferably trichloro-C2 to C18-alkyls,methoxy or ethoxy silane-C2 to C18-alkyls and thiol-C2 to C18-alkyls.The mixed monolayer also includes a specific concentration ofα,ω-functionalized molecules selected from the group that haveα-functionalizations such as chloro-silanes, ethoxysilanes,methoxysilanes, and thiols, and ω-functionalizations such as amino,carboxy, nitrile, cyanide, anhydride, epoxide, and hydroxy. Theconcentration of the mixed monolayers, as defined by the molar ratio ofthe ω-functionalized molecules to the methyl-terminated molecules,determines the grafting density of the end-tethered polymer. In a morepreferred aspect, the grafted polymer is that of formula (1) wherein(m/n)=4/3, the substrate material is glass and the self assembledmonolayer is aminopropyltriethoxy silane. In another more preferredaspect, the grafted polymer is any of those of formula (2) wherein(m/n)=13/3, of formula (3), and wherein (m/n)=13/5, of formula (4)wherein m=13.

The invention also relates to a microfluidic device that includes atemperature responsive polymer decorating one or more of themicrofluidic channel walls. In a preferred aspect, the device includes aglass substrate bearing a grafted polymer thereon, electrodes in contactwith the substrate, a fluid therebetween, a microchannel grid in contactwith the substrate whereby micro channels of the grid face the substrateand cover the electrodes to confine the conductive fluid to themicrochannels. The grafted polymer is that of formula 2 where m=13 andn=6.

Having summarized the invention, the invention will now be described indetail below by reference to the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Materials

All chemicals, unless otherwise stated, were purchased fromSigma-Aldrich and used as received.

The term “thermally-sensitive” as used herein refers to a molecule whichchanges in conformation or properties in response to changes inenvironmental temperature. As used herein, the term refers to moleculeswhich exhibit such changes in the temperature range of about 6° C. toabout 120° C., where the transition temperature is controlled by thepolymer composition and microstructure.

The term “lower critical solution temperature” (LCST) generally refersto the basic thermodynamics of polymer mixtures and polymer solutions,and represents the lower point at which polymer mixtures or solutionsseparate into two phases. LCST refers to one particular concentration(critical concentration) of the mixture or solution, where the phaseseparation occurs at the lowest temperature. For all otherconcentrations the transition temperature is referred to as binodalpoint or cloud point. See generally, Kroschwitz, ed, Kirk-OthmerEncyclopedia of Chemical Technology John Wiley & Sons New York19:837-904 (4^(th) ed., 1996); Hoffman, A. “Intelligent Polymers” inPark, K, ed., Controlled Drug Delivery: Challenges and Strategies,American Chemical Soc., Washington, D.C. (1997). As used herein, cloudpoint means the temperature at which a polymer (whether a homopolymer ora copolymer) undergoes phase transition from soluble to insoluble.Specifically, below the cloud point, the polymer is soluble in waterand, above it, the polymer precipitates from the solution.

The temperature sensitive, water soluble polymers of the inventioninclude polyesters, polyamides and polyanhydrides, preferably polyestersof formula (1)

where 1≦m≦30 ethylene oxide and 1≦n≦30 ethylene, the polyester offormula (2)

where 1≦m≦30 ethylene oxide and 1≦n≦30 ethylene, and polyamides offormula (3)

where 1≦m≦40 ethylene oxide and 1≦n≦30 ethylene, and

the polyamides of formula (4) where 1≦m≦40 ethylene oxide.

In the polymers of formulae (1)-(4) the monomer structure includeshydrophillic groups and hydrophobic components that are alternatedacross the polymer and interconnected (to each other and among the same)by linking groups. The hydrophilic and hydrophobic groups may alternate(as in formulae (1)-(4)) or may be randomly distributed in the backbone,side chains, and/or branches of the polymer. The polymers may includeuncross-linked chains or may be a cross-linked network. The temperaturesensitive polymers show a sharp LCST, and/or transition between swollenand collapsed chain conformations in solution, at a specific transitiontemperature for each polymer.

Control of the LCST of the temperature sensitive polymers entails twodesign principles: (1) control of the composition of the polymer bycontrol of the m/n fraction (where, m is the number of hydrophilicgroups, and n is the number of hydrophobic groups which constitute thepolymer), and (2) dispersment of the hydrophilic and hydrophobic groupsin the polymer structure so that there are preferably less than 30-50similar (all hydrophobic or all hydrophilic) group units bondedtogether. The temperature sensitive polymers may have blocks, grafts,branches, and the like, but in these embodiments the blocks, grafts, andbranches preferably are free of large sequences of hydrophilic only (orhydrophobic only) groups.

The hydrophilic groups may include a wide variety of hydrogen-bonding,water-soluble groups. Most preferably, the hydrophilic group is ethyleneoxide (EO). Other useful hydrophilic groups include methylene oxide,vinyl alcohol, acrylamide, acrylate, propylene oxide, and weak organicacids such as acrylic-acid, methacrylic-acid, methyl-acrylic-acid andthe like.

Numerous compounds may be used as a source of the hydrophillic group.Where EO is the hydrophilic group, useful source compounds include anypolymerizable small molecule that includes the above mentioned m numberof EO groups, such as ethylene oxide, difunctional oligo(ethylene oxide)molecules, and polymerizable monomer with pending oligo(ethylene oxide)groups, preferably but not limited to ethylene oxide, oligo(ethyleneoxide)-diamines, oligo(ethylene oxide)-diacids, oligo(ethyleneoxide)-diols, oligo(ethylene oxide)-divinyls, oligo(ethyleneoxide)-diepoxides, oligo(ethylene oxide) amino acids, and the like

Where methylene oxide is the hydrophilic group, useful source compoundsinclude polymerizable molecules which contain methylene oxide groups,such as difunctional oligo(methylene oxide), vinyl monomers whichinclude oligo(methylene oxide), and polymerizable molecules whichinclude pending oligo(methylene oxide), preferably oligo(methyleneoxide) diacids, oligo(methylene oxide)-diols, oligo(methyleneoxide)-diacids, oligo(methylene oxide)-diepoxides, oligo(methyleneoxide)-amino acids, and the like.

Where vinyl alcohol is the hydrophilic group, useful source compoundsinclude polymerizable molecules which contain vinyl alcohol groups, andpolymerizable molecules which contain groups which may be transformed tovinyl-alcohols, as for example vinyl acetate, preferably vinyl alcohol,vinyl acetate, difunctional vinyl acetates.

Where weak organic acids are the hydrophobic groups, useful sourcecompounds include polymerizable molecules which contain acrylic and/ormethacrylic acid, and polymerizable molecules which contain groups whichmay be transformed to the same acids, preferably acrylic acid,oligo(acrylic acid), difunctional-oligo(acrylic acid), methyl acrylate,methyl methacrylate, and combinations of thereof.

A wide variety of compounds also may be used as a source of thehydrophobic group and the linking group. Examples of hydrophobic groupswhich may be used include but are not limited to the following groupsand the combinations of two or more thereof: aliphatic groups preferablyoligomers of 1-20 units of ethylene, or propylene, or isobutelene,and/or mixtures of thereof, C4-C10 cycloaliphatic groups preferablycyclopropane, cyclobutane, cyclopentane, cyclohexane, furan, vinylgroups, acrylic groups such as acrylonitriles, methyl-methacrylate, andsemi-inorganic acrylic, aromatic groups such as benzene, phenylene,carbohydrate groups such as amylose, cellulose, cellulose nitrade, dienegroups such as butadiene, chlorotrene, isoorene, norbornene, anhydritegroups or pending anhydride groups, amine groups such as primary,secondary, tertiary, quaternary amines, imines, amino acids, DNA/RNAbases, and heterocyclic amines, imide groups, amide groups, estergroups, ether groups, ketone groups, sulfone and ether sulfone groups,nitrile groups, peptide groups such as protein groups, alanine,glutamate, collagen, gelatin, glycine, and lysine, saccharide groups,silane groups such as methyl-phenyl-silylene, mono-alkyl- anddi-alkyl-silylene, silazane groups such as silazane, mono-alkyl- anddialkyl-silazane, urethane groups, urea groups, vinylidene groups suchas chlorides, fluorides, isobutylene, multi-fluoro- andmulti-chloro-alkenes, and fluoropolymer groups such astetrafluoro-ethylene, perfluorinated and semifluorinated ethers, fluorovinyledenes, perfluorinated and semifluorinated aromatic rings, andperfluorinated or semifluorinated C4-C10 cyclo aliphatics.

The linking groups may include aliphatic carbon-carbon bonds, alkylenecarbon-carbon bonds, alkyne carbon-carbon bonds, imides, anhydrides,ureas, urethanes, sulfones, ethers, carbonates, peptide bonds, oxygen,sulfur, dienes, aromatic bonds/groups, ketones, silane/siloxane links,acrylics, and the like, preferably esters, amides, and anhydrides.

In a preferred aspect, where the hydrophobic group is ethylene and thelinking group is an ester, useful compounds for providing thehydrophobic groups include diacids and dialcohols of the hydrophobicgroups, preferably C1-C50-alkene-diacid and C1-C50 alkene dialcohols,and cycloaliphatic-diacids.

In a preferred aspect, where the hydrophobic group is ethylene and thelinking group is an amide, useful compounds for providing thehydrophobic group include diacids and diamines of these groups,preferably C1-C50-alkene-diacid and C1-C50 alkene diamines,cycloaliphatic-diacids, and cycloaliphatic diamines.

In a preferred aspect, where the hydrophobic group is ethylene and thelinking group is an anhydride, useful compounds for providing thehydrophobic group include diacids, diacid chlorides, anhydrates anddianhydrides of these groups, preferably C2-C10 alkane acid chloride,maleic anhydride, aromatic anhydrides and dianhydrides.

The temperature sensitive polymers show a sharp LCST in a variety ofsolvents and in the presence of a wide variety of additives. Usefulsolvents contain entities which hydrogen bond to hydrophilic groups suchas ethylene oxide. Useful solvents include water, alcohols such asmethanol, ethanol, propanol, isopropanol, butanol, and THF as well asmixtures thereof. Advantageously, various additives may be included inthe polymer solutions without affecting the nature of the LCSTtransition behavior of the polymer, although the temperature onset ofthe transition may be affected. Examples of these additives include butare not limited to salts preferably such as sodium chloride, potassiumchloride, buffer solutions and their components, biological serums andtheir components, organic acids such as acetic acid, propanoic acid,butanoic acid benzoic acid, inorganic acids such as sulfuric acid,hydrogen chloride, bases such as sodium hydroxide, potassium hydroxide,lithium hydroxide, calcium hydroxide, organics such as hexane, toluene,DMSO, acetonitrile, ethane diol, and crystalline and/or colloidalinorganics such as silica, alumina, silicates, and the similar.

Synthesis

The temperature responsive polymers of may be made by Chain-GrowthPolymerization by using two alternative methods. In the first methodrefereed to as the alternating polymer microstructure method, copolymersare synthesized using two or more types of short molecules that arecomplementary multi-functional. For example, one monomer has twofunctional groups A, and the other monomer has two functional groups B,where A-B can react but A-A and B-B cannot react (that is, thefunctional groups react only with each other, and do not react with thesame). Where one molecule contains hydrophilic groups and othermolecule(s) contain hydrophobic groups, this method produces analternating sequence of hydrophilic-alt-hydrophobic components, and theA-B reaction product will be the linking group. Where all of themolecules are bifunctional, linear polymer chains will be formed. Whereany of the molecules have more than two functional groups, e.g.trifunctional or tetrafunctional, branching and cross-linking results.

In a second method referred to as the random polymer microstructure,random copolymers are synthesized using two or more types of shortmolecules that are multi-functional, e.g. the one molecule contains Aand B functional groups and the other molecule contains C and Dfunctional groups, where all functional groups chosen to react with eachother (that is, A reacts with B, C, and/or D; B reacts with A, C, and/orD, etc). In this embodiment, the functional group pairs have similarreactivity so as to promote random sequences and depress block- orhomo-polymer sequences. Where one molecule contains hydrophilic groupsand the other molecule(s) contain hydrophobic groups, this methodproduces a random sequence of hydrophilic-random-hydrophobic components,and the A-B-C-D reaction products are linking groups. Where allmolecules are bifunctional, linear polymer chains are formed. Where anyof the molecules have more than two functional groups, e.g.trifunctional or tetrafunctional, branching and cross-linking result.Examples of monomers which may be used in this method includeamino(m)(ethylene oxide) carboxylic acid, amino(n)ethylene carboxylicacid, hydroxy(m)(ethylene oxide) carboxylic acid, hydroxy(n)ethylenecarboxylic acid and similar.

The polymers of the invention also may be produce by additionpolymerization. In this method, copolymers that include hydrophilic andhydrophobic components are synthesized by addition polymerization (e.g.free radical, anionic, cationic, catalyst assisted, ring opening, andthe similar) of two or more appropriate molecules. Such moleculescontain sites wherefrom addition polymerization can propagate (e.g.double or triple carbon bonds, or ring molecules, etc), and one of themcontains hydrophilic groups and the other contains hydrophobic groups.The reactivity ratios and the feed in the corresponding copolymerequation are chosen (or set by the reaction conditions) to promoterandom or alternating sequences and depress block- or homo-polymersequences [see for example: chapter 5 of P. C. Painter and M. M. Coleman“Fundamentals of Polymer Science” Technomic Publishing Co, 2^(nd)edition, 1997]. Where one molecule contains hydrophilic groups and theother molecule(s) contain hydrophobic groups and the reactivity ratiosare all set to zero or to very small values close to zero, alternatingsequences are mainly produced. Where one molecule contains hydrophilicgroups and the other molecule(s) contain hydrophobic groups, and thereactivity ratios are all set to one or to values very close to one,random sequences are mainly produced, with a copolymer composition thatreflects that of the feed. Where cross-linking groups are introducedand/or chain transfer to the chain and/or short chain branching canoccur, branching and cross-linking results.

Synthesis of the temperature sensitive polymers advantageously entailscontrol of the fractions of the hydrophilic groups and the hydrophobicgroups which constitute the polymer, and control of the polymermicrostructure. The hydrophilic and hydrophobic groups are welldispersed in the polymer, and are preferably less than 20-50 similar(all hydrophobic or all hydrophilic) group units bonded together. Thepolymer may have blocks, grafts, branches, and the like, but in theseembodiments each of the blocks, grafts, and branches preferably are freeof large sequences of hydrophilic only (or hydrophobic only) groups.

Depending on the chemistry of the polymer molecule where a hydrophilicgroup such as EO is incorporated, different synthesis schemes may beused to make the polymer. For example, difunctional molecules such asdiamines, dialcohols, diacids, organometalics and combinations thereof,such as amino acids, which include hydrophobic groups such as ethylene(“EE”), and complementary difunctional molecules which includehydrophilic groups such as EO may be polymerized by chain-growth schemessuch as polycondensation.

Where the hydrophilic and/or hydrophobic groups are included in vinylmolecules or rings, polymerization may be performed by chain-additionschemes such as free radical polymerization, cationic/anionicpolymerization, and catalyst-aided polymerization.

The invention will now be illustrated in further detail below byreference to the following non-limiting examples:

EXAMPLES 1-5 Polyesters of Formula (1)

The polyesters of formula (1) generally may be produced by apolycondensation reaction where poly(m)ethylene glycol is reacted withdicarboxychloride poly(ethylene). In these examples, m represents thenumber of EO groups and n represents the number of EE groups.

Example 1 Synthesis of Polyester of Formula (1) where Ratio of (m/n)=4/3

0.01 mol of poly(ethylene glycol), MW=200 g/mol is mixed with 0.005 molof 1,6-hexanedicarboxychloride (suberoyl chloride) in 40 mL oftetrahydrofuran (THF) solvent to form a solution. Solid NaOH, in anamount of 0.2 g, is present in the solution as a catalyst. The solutionis heated to 90° C. Then, an additional 0.005 mol of1,6-hexanedicarboxychloride is added drop-wise over a period of 2 hoursto the solution. The resulting solution is maintained under refluxconditions at 90° C. for 10 hours. The THF solvent is fully evaporatedand the residue is deposited into 100 mL of absolute ethanol to form asecond solution. The second solution is placed into a separatory funnelwhere insoluble inorganic side products (e.g. NaCl) are separated fromthe polymer solution in absolute ethanol. The ethanol is evaporated at50° C. to obtain the polyester of formula (1) where m/n=4/3. The highmolecular weight fractions of the polyester (degree of polymerizationmore than 100) are separated using centrifuge.

Example 2 Synthesis of Polyester of Formula (1) where Ratio of (m/n)=5/3

The procedure of example 1 is emploved except that poly(ethylene glycol)of Mw=250 g/mol is used for reaction with 1,6-hexanedicarboxychloride.

Example 3 Synthesis of Polyester of Formula (1) where Ratio of(m/n)=13/3

The procedure of example 1 is employed except that poly(ethylene glycol)of Mw=600 g/mol is used for reaction with 1,6-hexanedicarboxychloride.

Example 4 Synthesis of Polyester of Formula (1) where Ratio of (m/n)=5/5

The procedure of example 1 is employed except that poly(ethylene glycol)of Mw=250 g/mol is used and 1,10-decanedicarboxychloride is substitutedon a 1:1 molar basis for 1,6-hexanedicarboxychloride.

Example 5 Synthesis of Polyester of Formula (1) where Ratio of(m/n)=13/5

The procedure of example 4 is employed except that poly(ethylene glycol)of Mw=600 g/mol is used for reaction with 1,10-decanedicarboxychloride

EXAMPLES 6-9 Synthesis of Polyesters of Formula (2)

Generally, the polyesters of formula (2) may be produced by chlorinatingα,ωbis(carboxymethyl)-poly(m)ethyleneoxide and reacting the productthereof with α,ω-diol-poly(n)ethylenes.

Example 6 Polyesters of Formula (2) where (m/n)=5/6

3.609 g of α,ωbis(carboxymethyl)-poly(m)ethyleneoxide (m=5), MW=250, ischlorinated with 4 mL of neat thionyl chloride. The chlorination is donein 100 mL THF at 80° C. for 12 hours while stirring to produce ethyleneoxide diacid chloride. The diacid chloride is extracted by evaporatingthe THF and unreacted thionyl chloride at 110° C. Then, all of theethylene oxide diacid chloride is dissolved in 50 mL THF and mixed with100 mL of a first solution formed from 2.9 g of 1,12 dodecane diol and200 mL THF in the presence of 0.2 g solid NaOH catalyst to produce areaction mixture. Then the mixture is allowed to react at 150° C. for 24hours. During the first 12 hours of the reaction an additional 100 mL ofthe first solution of 1,12-dodecane diol and THF is added dropwise tothe reaction mixture. The resulting polyester of formula (2) where m=5and n=6 is separated from the inorganic side products and unreactedmonomers by using the procedure as used in Example 1.

Example 7 Polyesters of Formula (2) where (m/n)=13/6

9.45 gms of α,ωbis(carboxymethyl)-poly(m)ethyleneoxide (m=13), MW=600,is chlorinated with 4 mL of neat thionyl chloride. The chlorination isdone in 100 mL THF at 80° C. for 12 hours while stirring to produceethylene oxide diacid chloride. The diacid chloride is extracted byevaporating the THF and unreacted thionyl chloride at 110° C. Then, allof the ethylene oxide diacid chloride is dissolved in 50 mL THF andmixed with 100 mL of a first solution formed from 2.9 g of 1,12-dodecanediol and 200 mL THF in the presence of 0.2 g solid NaOH catalyst toproduce a reaction mixture. Then the mixture is allowed to react at 150°C. for 24 hours. During the first 12 hours of the reaction an additional100 mL of the first solution of 1,12-dodecane diol and THF is addeddropwise to the reaction mixture. The resulting polyester of formula (2)where m=13 and n=6 is separated from the inorganic side products andunreacted monomers by the procedure used in Example 1.

Example 8 Polyesters of Formula (2) where (m/n)=5/3

3.6 gms of α,ωbis(carboxymethyl)-poly(m)ethyleneoxide (m=5), MW=250, ischlorinated with 4 mL neat thionyl chloride. The chlorination reactionis done in 100 mL THF at 80° C. for 12 hours while stirring to produceethylene oxide diacid chloride. The diacid chloride is extracted byevaporating the THF and unreacted thionyl chloride at 110° C. Then, allof the ethylene oxide diacid chloride is dissolved in 50 mL THF andmixed with 25 mL of a first solution formed from 1.71 g of 1,6-hexanediol and 50 mL THF in the presence of 0.2 g solid NaOH catalyst toproduce a reaction mixture. Then the mixture is allowed to react at 150°C. for 24 hours. During the first 12 hours of the reaction an additional25 mL of the first solution of 1,6-hexane diol and THF is added dropwiseto the reaction mixture. The resulting polyester of formula (2) wherem=5 and n=3 is separated from the inorganic side products and unreactedmonomers by using the procedure used in Example 1.

Example 9 Polyesters of Formula (2) where (m/n)=13/3

9.45 gms of α,ωbis(carboxymethyl)-poly(m)ethyleneoxide (m=13), MW=600,is chlorinated with 4 mL of neat thionyl chloride. The chlorination isdone in 100 mL THF at 80° C. for 12 hours while stirring to produceethylene oxide diacid chloride. The chloride is extracted by evaporatingthe THF and unreacted thionyl chloride at 110° C. Then, all of theethylene oxide diacid chloride is dissolved in 50 mL THF and mixed with25 mL of a first solution formed from 1.86 g of 1,6-hexane diol and 50mL THF in the presence of 0.2 g solid NaOH catalyst to produce areaction mixture. Then the mixture is allowed to react at 150° C. for 24hours. During the first 12 hours of the reaction an additional 25 mL ofthe first solution of 1,6-hexane diol and THF is added dropwise to thereaction mixture. The resulting polyester of formula (2) where m=13 andn=3 is separated from inorganic side products and unreacted monomers byusing the procedure employed in Example 1.

Example 9A Poly(Ethylene Oxide) Made Without Use of Hydrophobic Monomer

For comparison, Poly(ethylene oxide) which is a polymer which includesan ether linking group is made. The Poly(ethylene oxide) is made usingthe anionic ring opening polymerization method. In this method, 0.01 molof sodium hydroxide and 0.01 mol of ethanol is added to a 10% aqueoussolution of ethylene oxide. The mixture is refluxed for 12 hours at 90C. Then the mixture is evaporated, and the residue is dissolved in 50 mLabsolute ethanol and filtered to remove inorganic side products. Thenthe polymer is recrystalized from the ethanol solution by mixing it with500 mL toluene.

EXAMPLES 10-14 Synthesis of Polyamides of Formula (3)

Generally, synthesis of the polyamides of formula (3) entails reactionof ethylene oxide diacid chloride and an aliphatic diamine. Synthesis ofvarious polyamides of formula (3) are shown below:

Example 10 Polyamide of Formula (3) where (m/n)=5/5

15.4 g bis(carboxymethyl)(5)-ethyleneoxide is chlorinated using 10 mL ofneat thionyl chloride in 100 mL of THF at 80° C. reflux for 12 hours.The resulting ethyleneoxide diacid chloride is extracted by evaporatingthe THF solvent and excess thionyl chloride at 110° C. The ethyleneoxidediacid chloride is dissolved in 100 mL chloroform and placed in an icebath (0° C.). 10.61 g of 1,10-diaminodecane is dissolved in 100 mL ofchloroform and is added to the ethylene oxide diacid chloride solutiondrop wise over the period of 12 hours while mixing. After all of the1,10-diaminodecane is added, the resulting solution is mixed for 6hours, and then slowly heated to 80° C. to evaporate the chloroform andto produce the polymer. Polymer separation is done as in example 1.

Example 11 Polyamide of Formula (3) where (m/n)=13/5

24.92 g bis(carboxymethyl)(13)-ethyleneoxide is chlorinated using 10 mLof neat thionyl chloride in 100 mL of THF at 80° C. reflux for 12 hours.The resulting ethyleneoxide diacid chloride is extracted by evaporatingthe THF solvent and excess thionyl chloride at 110° C. The ethyleneoxidediacid chloride is dissolved in 100 mL chloroform and placed in an icebath (0° C.). 7.18 g of 1,10-diaminodecane is dissolved in 100 mL ofchloroform and is added to the ethylene oxide diacid chloride solutiondrop wise over the period of 12 hours while mixing. After all of the1,10-diaminodecane is added, the resulting solution is mixed for 6hours, and then slowly heated to 80° C. to evaporate the chloroform andto produce the polymer. Polymer separation is done as in example 1.

Example 12 Polyamide of Formula (3) where (m/n)=13/3

24.92 g bis(carboxymethyl)(13)-ethyleneoxide is chlorinated using 10 mLof neat thionyl chloride in 100 mL of THF at 80° C. reflux for 12 hours.The resulting ethyleneoxide diacid chloride is extracted by evaporatingthe THF solvent and excess thionyl chloride at 110° C. The ethyleneoxidediacid chloride is dissolved in 100 mL chloroform to produce anethyleneoxide diacid chloride solution and placed in an ice bath (0°C.). 4.83 g of 1,6-diaminohexane is dissolved in 100 mL of chloroformand is added to the ethylene oxide diacid chloride solution drop wiseover the period of 12 hours while mixing. After all of the1,6-diaminohexane is added, the resulting solution is mixed for 6 hours,and then slowly heated to 80° C. to evaporate the chloroform and toproduce the polymer. Polymer separation is done as in example 1.

EXAMPLES 13-14 Polyamides of Formula (4)

Generally, manufacture of the polyamides of formula(4) entail reactionof ethylene oxide diacid chloride and an alkylenecycloaliphatic amine.Manufacture of various polyamides of formula (4) are shown below:

Example 13 Polyamide of Formula (4) where (m/n)=5/4 where n=4 is theThermodynamic Equivalent of the Cycloaliphatic Hydrophobic Group of aLinear Ethylene

21 g bis(carboxymethyl)(5)-ethyleneoxide is chlorinated using 10 mL ofneat thionyl chloride in 100 mL of THF at 80° C. reflux for 12 hours.The resulting ethyleneoxide diacid chloride is extracted by evaporatingthe THF solvent and excess thionyl chloride at 110° C. The ethyleneoxidediacid chloride is dissolved in 100 mL chloroform to produce anethyleneoxide diacid chloride solution and placed in an ice bath (0°C.). 17.4 g of 4,4′-methylene-bis(cyclo-hexanamine) is dissolved in 100mL of chloroform and is added to the ethylene oxide diacid chloridesolution drop wise over the period of 12 hours while mixing. After allof the 4,4′-methylene-bis(cyclo-hexanamine) is added, the resultingsolution is mixed for 6 hours, and then slowly heated to 80° C. toevaporate the chloroform and to produce the polymer. Polymer separationis done as in example 1.

Example 14 Polyamide of Formula (4) where (m/n )=13/4 where n=4 is theThermodynamic Equivalent of the Cycloaliphatic Hydrophobic Group of aLinear Ethylene

24.92 g bis(carboxymethyl)(13)-ethyleneoxide is chlorinated using 10 mLof neat thionyl chloride in 100 mL of THF at 80° C. reflux for 12 hours.The resulting ethyleneoxide diacid chloride is extracted by evaporatingthe THF solvent and excess thionyl chloride at 110° C. The ethyleneoxidediacid chloride is dissolved in 100 mL chloroform to produce anethyleneoxide diacid chloride solution and placed in an ice bath (0°C.). 8.72 g of 4,4′-methylene-bis(cyclo-hexanamine) is dissolved in 100mL of chloroform and is added to the ethylene oxide diacid chloridesolution drop wise over the period of 12 hours while mixing. After allof the 4,4′-methylene-bis(cyclo-hexanamine) is added, the resultingsolution is mixed for 6 hours, and then slowly heated to 80° C. toevaporate the chloroform and to produce the polymer. Polymer separationis done as in example 1.

Example 15 Polyanhydride where (m/n)=13/3

0.1 mol bis(carboxymethyl)(13)-ethyleneoxide is chlorinated using 0.2mol of neat thionyl chloride in 100 mL of THF at 80° C. reflux for 12hours. The resulting ethyleneoxide diacid chloride is extracted byevaporating the THF solvent and excess thionyl chloride at 110° C. Theethyleneoxide diacid chloride then is dissolved in 100 mL dimethylchloride and placed in an ice bath (0° C.). 0.01 mol of triethylamine isadded to the solution and used as a catalyst.

0.1 mol of octanedioic acid is dissolved in 100 mL of dimethyl chlorideand is added to the ethylene oxide diacid chloride solution drop wiseover the period of 12 hours while mixing. After all of the octanedioicacid is added, the resulting solution is mixed for 6 hours, and thenslowly heated to 80 C to evaporate the dichloromethane and to producethe polymer. Polymer separation is done as in example 1.

The anhydride polymer produced has the structure of formula (5) where(m/n)=13/3:

Characterization

The polyesters of formulae (1) and (2) are characterized by aqueous gelpermeation chromatography (GPC) with a Polymer Laboratories GPC, bearingPL Aquagel-OH columns. A set of various molecular weightpoly(ethyleneoxide) standards are used for the calibration of the GPC.The polyamides of formulae (3) and (4) are characterized by static lightscattering using ethanol solutions by Dawn DSP-F Laser Photometer ofWyatt Technology. Molecular weights and polydispersities are given intables 1A-1C.

TABLE 1A Polyesters of formulae 1 and 2 MW, g/mol Polydispersity (MW/Mn)Example no. 1: m/n = 4/3 300,510 1.83 Example no. 2: m/n = 5/3 247,0802.06 Example no. 7: m/n = 13/6 575,050 1.33 Example no. 9: m/n = 13/3377,860 3.04

TABLE 1B Polyamides of formula 3 MW, g/mol Polydispersity (MW/Mn)Example no. 10 m/n = 5/5 104,000 1.42 Example no. 11 m/n = 13/5 — —Example no. 12 m/n = 13/6 112,000 1.36

TABLE 1C Polyamides of formula 4 MW, g/mol Polydispersity (MW/Mn)Example no. 13: m/n = 5/4 426,000 1.65 Example no. 14: m/n = 13/4769,000 1.73Cloud point (CP) measurements were performed in a water heat bath inwhich a 2 mL vial holding a sample of the polymer aqueous solution isimmersed. The temperature of the sample is varied at a heating/coolingrate of 0.2° C./min. The temperature of the sample is measured by athermocouple. A red light (650 nm) semiconductor laser (2 mW) passeslight through the sample for detection by a Metrological photo-detectorthat has an accuracy of 1 μW. In order to remove any influence of heatbath turbulence, the last digit of the measurement is ignored (higherorder digits exhibited insensitivity to water turbulence) resulting inmeasurement accuracy of 0.01 mW. The cloud points of examples 1-9A inwater are shown in Table 2.

TABLE 2 Cloud Point Temperatures Transition temperature, Polymer ofHydrophilic Hydrophobic (m/n) Linkage ° C. (at 0.1% aqueous Example No.group group ratio group solution)  1 Ethylene Oxide Ethylene 4/3 Ester18  2 Ethylene Oxide Ethylene 5/3 Ester 21  7 Ethylene Oxide Ethylene13/6  Ester 26  9 Ethylene Oxide Ethylene 13/3  Ester 46  9A EthyleneOxide <none> 1/0 Ether 120 10 Ethylene Oxide Ethylene 5/5 Amide 6.6 11Ethylene Oxide Ethylene 13/5  Amide 43 12 Ethylene Oxide Ethylene 13/3 Amide 60 13 Ethylene Oxide Methylene- 5/4 Amide 25 biscyclohexanamine 14Ethylene Oxide Methylene- 13/4  Amide 64 biscyclohexanamine

The polymers of the invention show a sharp transition temperature. Toillustrate, the transition behavior of the polyester polymer of Example7 where m/n=13/6 is shown in Tables 3 and 3A.

TABLE 3 0.1 wt. % Fraction 0.15 wt. % Fraction 0.75 wt. % Fraction 1.0wt. % Fraction laser laser laser laser Intensity, Intensity, Intensity,Intensity, Temp. °K mW Temp. °K mW Temp. °K mW Temp. °K mW 294.2 0.968279.3 0.85 291 1.088 289 0.889 295.3 0.97 280 0.849 292 1.084 290 0.888296 0.972 281 0.849 293 1.085 291 0.889 297 0.968 282 0.851 294 1.083292 0.889 298 0.967 283 0.852 295 1.082 293 0.888 299 0.963 284 0.852296 1.08 294 0.886 300 0.953 285 0.85 297 1.075 295 0.885 301 0.936 2860.851 298 1.07 296 0.886 302 0.916 287 0.849 299 1.061 297 0.886 302.50.9 288 0.848 300 1.052 298 0.88 303 0.89 289 0.847 300.6 0.955 2990.886 303.5 0.882 290 0.846 301 0.536 299.9 0.646 304 0.862 291 0.843301.5 0.09 300. 0.501 304.5 0.853 292 0.841 302 0.041 300.1 0.409 3050.843 293 0.842 302.2 0.012 300.2 0.266 305.5 0.83 294.5 0.84 303 0.05300.3 0.136 306 0.815 295 0.836 304 0.02 300.4 0.086 306.5 0.8 295.50.836 304.5 0.02 300.5 0.05 307 0.782 296 0.836 305 0.02 300.6 0.03307.5 0.773 297 0.83 300.7 0.016 308 0.755 297.5 0.83 300.8 0.011 3090.726 298 0.82 300.9 0.007 310 0.708 298.2 0.761 301 0.006 311 0.685298.3 0.639 301.1 0.005 312.5 0.636 298.5 0.421 301.3 0.004 313 0.619298.6 0.28 301.5 0.003 314 0.597 301.6 0.003 315 0.569 301.7 0.003 3160.54 317 0.515 318 0.492 319 0.468 320.3 0.443 321.2 0.43 322 0.414 3230.396 324 0.372 325.5 0.35 326.2 0.339

TABLE 3A 10. wt. % Fraction 15 wt. % Fraction 20. wt. % Fraction 40 wt.% Fraction laser laser laser laser Intensity, Intensity, Intensity,Intensity, Temp. °K mW Temp. °K mW Temp. °K mW Temp. °K mW 293.5 0.878295.7 0.886 299 0.851 297.5 0.887 294. 0.874 296 0.889 300 0.84 2980.882 295. 0.868 297 0.893 301 0.84 298.5 0.879 296 0.868 298 0.889 3020.838 299 0.871 297 0.867 299 0.889 303 0.833 299.5 0.87 298 0.866 3000.886 304 0.827 300 0.87 299 0.863 301 0.882 305 0.822 301 0.87 300 0.86302 0.872 306 0.815 302 0.87 301 0.853 303 0.86 307 0.793 303 0.873 3020.844 304 0.862 307.5 0.775 304 0.87 303 0.833 305 0.845 308 0.758 3050.869 304 0.822 306 0.825 308.5 0.736 306 0.865 305 0.794 307 0.795 3090.7 307 0.864 305.5 0.771 307.5 0.76 309.1 0.678 308 0.866 306 0.734 3080.76 309.2 0.669 309 0.866 306.5 0.72 308.5 0.58 309.3 0.656 310 0.862306.6 0.708 309.1 0.028 309.4 0.64 311 0.865 306.7 0.045 309.2 1.00E−03309.5 0.625 312 0.863 306.8 0.004 309.6 0.603 313 0.858 306.9 1.00E−03309.7 0.553 314 0.864 307 0.726 309.8 0.552 315 0.855 309.9 0.484 3160.82 0.47 316.4 0.775 0.458 317 0.039 0.438 317.1 1.00E−03 0.403 0.2140.16 0.072 1.00E−03Surface Grafted Temperature Responsive Polymers

In another aspect, the temperature responsive polymers are grafted ontothe surface of a substrate by use of a self assembled monolayer (SAM)that is previously deposited onto a substrate such as metal, polymer,glass or silicon. Examples of molecules that may be used for the SAM areα-/chloro- or ethoxy- or methoxy-/silanes-ω-/amino or carboxy or nitrileor cyanide or hydroxy/alkyls, or the respective ω-functionalizedα-thiols. SAM can be formed using the a single species or a mixture ofthe above mentioned molecules. The composition of the mixture allows tocontrol surface grafting density of the polymer to be end-graftedthereon. Yet in another way to control grafting density, reaction ofsingle species SAM with a mixture of organic difunctional andmonofunctional compounds, where the reaction is possible through theω-functionality of the SAM and the end-grafting of the polymers willoccur only from the difunctional molecules.

The grafted polymer may be grown on the SAM by two methods. In bothmethods, the end-groups of the polymer and the active groups of the SAMmay be interchanged with any pair of groups which may react to producegrafting. In a first method, growth of temperature responsive graftedpolymer which has hydrophobic and hydrophilic alternations may beachieved by immersion of the treated substrate that bears a SAM layerinto a 10% solution of ethylene oxide diacid chloride (m=13 or m=5). Theimmersion is done in chloroform at room temperature for a period of 5min, and the surface then is washed with chloroform for a period of 10min. Then the treated substrate bearing the SAM layer is immersed into a10% solution of a dodecane diol or hexane diol (n=6 or n=3 hydrophobicgroups correspondingly) in chloroform for a period of 5 minutes andsurface is washed with chloroform for 10 min. Growth of the polymer maybe achieved by repeating the above cycle, i.e., (immersion in theoligo(ethylene oxide) diacid solution for 5 mn, washing, immersion inoligo(ethylene)-diol solution, washing) until the desired polymer lengthis reached.

After completion of a set of 50 of the above cycles, the treatedsubstrate, which now bears end-tethered polymers, is washed withchloroform, ethanol and water, and further ultrasonically cleaned inneat chloroform for a period of 5 minutes and then in DD water for aperiod of five minutes to remove any non-grafted molecules.

In a second method, growth of grafted polymer may be achieved by using asubstrate bearing a mixed-SAM that has a controlled surface density offunctional ω-groups, such as alcohols, amines, carboxylic acids, andcarboxylic-acid-chlorides. The treated substrate is immersed for aperiod of 15 minutes at room temperature into a 5 wt % solution ofseparately synthesized polymer (e.g., polyester (m/n)=13/6 or polyester(m/n)=13/3, as described in the examples 6 and 9) bearing aend-functional group able to react with the SAM ω-functionality.

Growth of Grafted Polymers

Prior to growth of grafted polymer, a SAM is generated on a substrate.The substrate may be, for example, a silicon wafer such as that fromMonsanto or a glass cover slide such as that from VWR, Inc. First thesubstrate is cleaned by immersion into a piranha etch that includessulfuric acid and hydrogen peroxide in a volume ratio of 50:1 at 120° C.for two hours, and then rinsing with distilled deionized (DD) water. Thesubstrate then is further cleaned in a RF plasma cleaner for fiveminutes. The substrate is subsequently immersed into 0.4% solution ofaminopropyltriethoxy silane (APTES) in toluene for 1 hour to form theSAM.

The SAM bearing substrate is subsequently washed with ethanol and withDD water, and then annealed in a vacuum oven overnight at 170° C. Thenthe SAM modified substrate is immersed in a 100 mL chloroform solutionof mixture of myristic acid chloride and ethyleneoxide diacid chloride(EO=5 and 13) containing 60/40 and 80/20 weight percent ratiosrespectively. This forms a surface with randomly distributed activesites wherefrom the end-tethering of the thermally sensitive polymers isenabled, thus allowing for control of the polymer grafting density.

Alternatively, a selected composition, for example a 20:80 ofω-functionalized and methyl-terminated surfactants may be deposited as aSAM directly in one step to effectively create a similar randomdistribution of active sites, wherefrom the end-tethering of thethermally sensitive polymers is enabled, thus also allowing for controlof the grafting density.

Growth of grafted polymers is further illustrated by reference to thefollowing non limiting examples:

Example 16 Growth of Polymer of Formula (1), where (m/n)=4/3 Onto aGlass Substrate Bearing a APTES SAM Layer

The substrate treated according the procedure described above isimmersed into the 10 wt % solution of 1,6-hexanedicarboxy chloride inchloroform for 5 minutes at room temperature. It then is washed withchloroform for 10 minutes and immersed into the 10 wt % solution ofoligo(ethylene glycol) Mw=200 g/mol in chloroform. Then the substrate isagain washed with chloroform and immersed in the first solution (i.e.solution of 1,6-hexane dicarboxy chloride). The cycle is repeated 50times. Then the substrate is cleaned as described above.

Example 17 Growth of Polymer of Formula (2), where (m/n)=13/3 Onto aGlass Substrate Bearing a APTES SAM Layer

The substrate treated according the procedure described in Example 16 issubjected to the polymer grafting procedure described in Example 16. Thebis(chlorocarboxymethyl)(13)-ethyleneoxide is used as a oligo(ethyleneoxide) diacid chloride and 1,6-hexane diol is used as a diol.

Example 18 Growth of Polymer of Formula (3), where (m/n)=13/5 Onto aGlass Substrate Bearing a APTES SAM Layer

The substrate treated according the procedure described in Example 16 issubjected to the polymer grafting procedure described above where theSAM modified substrate is treated with the solution of mixture ofmyristic acid chloride. Polymer of a formulae (3) containing m=13ethylene oxide groups and n=5 ethlyene groups is synthesized separatelyas described in Example 11.

Example 19 Growth of Polymer of Formula (4), where (m/n)=13/4 Onto aGlass Substrate Bearing a APTES SAM Layer

The substrate is treated and the polymer is grafted as in example 18except that 4,4′-methylene-bis(cyclo-hexanamnine) is used instead ofdiol.

The grafted polymers are characterized by water contact anglemeasurements by sessile drop method using FT Å2000 (First Ten AngstromsInc.) contact angle and surface tension measurement system and atomicforce microscope (AFM) PicoScan (Molecular Imaging Inc.) and NanoscopeIII (Veeco) adhesion measurements under water. Each of thesemeasurements shows that the sharp temperature response of the polymersis retained after having been grafted. The measurements also show thatthe control of the transition temperature depends on (m/n) fraction(where, m is the number of hydrophilic groups, and n is the number ofhydrophobic groups which constitute the polymer). In addition, thetemperature response of the polymer is independent of the polymergrafting density, the type of grafting group which includes but is notlimited to functional end groups of the SAM preferably amine, hydroxyl,carbonyl, nitrile and vinyl, the molecular weight of the graftedpolymer, the substrate material and geometry, as well as the SAMchemistry and geometry.

Advantageously, as shown in Tables 4, 5A and 5B, the temperatureresponse of the grafted polymers enables switching the surface energyand surface adhesion between different values which correspond toextended and collapsed chain conformations of the grafted polymer.

Advantageously, the grafted polymers may achieve temperature responsiveadsorption/release of synthetic molecules, biomolecules, proteins,cells, droplets, particles and the like from the surface of the SAMlayer on the substrate.

TABLE 4 Contact Angle Measurements Data of Surface Adhesion Energy forPolyester of Formula (2) of Example 7 where (m/n) = 13/6 Temperature, °C. Adhesion energy, J 79 0.10035 60 0.10695 46 0.11231 38 0.11539 290.12107 24 0.13432

TABLE 5A AFM measurement data of adhesion energy of Polyester of Formula(2) of Example 9 where (m/n = 13/3) Temperature, ° C. adhesion energy, J24 7.2502E−4 37.5 5.38748E−4 45.3 5.81031E−4 54 3.26203E−4 63.22.49078E−4

TABLE 5B AFM measurement data of adhesion energy of Polyester (2) ofExample 7 where m/n = 13/6 Temperature, ° C. adhesion energy, J 175.12934E−4 21 6.17733E−4 23 5.32335E−4 26 6.4147E−4 35 1.40377E−4 459.83022E−5

The surface grafted, temperature responsive polymers of the inventionmay be employed in a variety of applications such as pharmaceutical,biotechnological, microelectromechanical and chemical applications suchas controlled drug delivery systems, DNA transfection applications, celladhesion regulation applications, chemical processing systems andmicrofluidic cells. A microfluidic cell includes a microchannel gridwhich may be made from poly(dimethylsiloxane) (PDMS). Electrodes may beattached on two opposing sides of the grid.

The microchannel grid can be made by pouring uncured PDMS into a moldthat has holes which measure 200 nm deep by 5 mm wide×5 mm long. ThenPDMS is cured for 2 hours at 65° C. The cured PDMS then is peeled fromthe mold and cured at 65° C. for an additional 10 hours. The surface ofthe micro channel grid is made hydrophilic by irradiating it with UVlight and/or oxygen plasma for 2 to 5 minutes.

Advantageously, the geometry and material of the channels in the grid donot affect the sharp transition temperatures of the polymers of theinvention. Grafting of a temperature responsive polymer onto themicrochannel grid of PDMS may be performed as described above inconnection with grafting of polymer onto a SAM on glass substrate.Grafting may be achieved directly onto the microchannel grid as well asonto the substrate where the fluidic geometry is attached. Manufactureof a microfluidic cell that employs the microchannel grid is illustratedin example 20.

Example 20

A glass substrate bearing a grafted polymer as produced in example 18 isplaced onto a controlled temperature stage device that automaticallymaintains a preset temperature with high accuracy. An example of such adevice is the “High Temperature Stage” from Molecular Imaging Corp.fitted with 321 Autotuning Temperature Controller of LakeshoreCryotronics Inc.

Electrodes are placed onto the surface of the substrate and 10 mL of0.01% solution of methylene blue is poured between the electrodes. Themicrochannel grid is fixed onto the substrate so that the micro channelsface the substrate and cover the electrodes to confine the methyleneblue solution to the microchannels. A voltage then is applied to theelectrodes. The applied voltage may vary with the fluidic material inthe microchannels. For instance, a voltage of 1-2 V is used with alkalications. a voltage of 1-3 V is used with cationic dyes; a voltage of1-12 V is used with DNA/RNA biomolecules. The extent of transport, e.g,ionic current, DNA mass, and the like is measured using PM2525multimeter of Fluke Inc. while varying the temperature of the substrate.

The ionic conductivity for methylene blue is measured by measuring theelectrical current generated by a 3V potential between the electrodes.The results are shown in Table 6.

TABLE 6 Conductivity measurement data of Polyester (2) of Example 7where m/n = 13/6 as a valve in a microfluidic channel Temperature, ° C.Current, μA 22 0.5511 23 0.629 24 0.6716 25 0.707 26 0.7311 27 0.7393 280.7457 31 0.7538 37 0.7642 42 0.766

1. A microfluidic device having a temperature responsive polymer and aconductive fluid comprising, a substrate bearing a grafted temperatureresponsive polymer thereon, electrodes in contact the substrate so as tocontain a conductive fluid therebetween, a microchannel grid in contactwith the substrate whereby micro channels of the grid face the substrateand cover the electrodes to confine the conductive fluid to themicrochannels, wherein the grafted polymer comprises one of thefollowing polymers:

wherein 1≦m≦30 and 1≦n≦30.
 2. The device of claim 1 wherein theconductive fluid comprises methylene blue.
 3. A temperature sensitive,water soluble polymer that has a lower critical solution temperature offrom about 7° C. to about 70° C., wherein the monomeric unit of thepolymer contains a number (m) of hydrophilic organic groups and a number(n) of hydrophobic organic groups, connected via organic linking groups.4. The temperature sensitive polymer of claim 3, where the hydrophilicgroup is ethylene oxide and the hydrophobic group is ethylene.
 5. Thetemperature sensitive polymer of claim 3, wherein the polymer has theformula:

wherein the number of hydrophilic groups (m) is between 1 and 30, andnumber of hydrophobic groups (n) is between 1 and
 30. 6. The temperaturesensitive polymer of claim 3, where the hydrophilic and hydrophobicgroups are randomly placed along a linear polymer molecule with the sameratio m/n and are not clustered in hydrophilic-only or hydrophobic-onlysequences with more than 30 homologous (hydrophilic or hydrophobic)groups in each sequence.
 7. An aqueous composition, comprising: a watersoluble polymer of claim
 3. 8. The aqueous composition of claim 7,wherein the hydrophilic component of the water soluble polymer isselected from the group consisting of: ethylene oxide, methylene oxide,vinyl alcohol, acrylamide, acrylate, propylene oxide, acrylic-acid,methacrylic-acid, and methyl-acrylic-acid.
 9. The aqueous composition ofclaim 7, wherein the hydrophobic component of the water soluble polymeris selected from the group consisting of: ethylene, or propylene, orisobutelene, C4-C10 cycloaliphatic, cyclopropane, cyclobutane,cyclopentane, cyclohexane, furan, vinyl groups, acrylonitriles,methyl-methacrylate, semi-inorganic acrylic, aromatic groups, benzene,phenylene, carbohydrates, amylose, cellulose, cellulose nitrade, dienegroups, butadiene, chloroprene, isoprene, norbornene, anhydride groups,DNA/RNA bases, ester groups, ether groups, ketone groups, sulfone andether sulfone groups, nitrile groups, peptide groups such as proteingroups, alanine, glutamate, collagen, gelatin, glycine, and lysine,saccharide groups, silane groups, methyl-phenyl-silylene, mono-alkyl-and di-alkyl-silylene, silazane groups, silazane, mono-alkyl- anddialkyl-silazane, vinylidene chlorides, vinylidene fluorides,isobutylene, multi-fluoro- and multi-chloro-alkenes, and fluoropolymergroups, tetrafluoro-ethylene, perfluorinated and semifluorinated ethers,fluoro vinyledenes, perfluorinated and semifluorinated aromatic rings,perfluorinated and semifluorinated C4-C10 cyclo aliphatics.
 10. A methodof controlling the lower critical solution temperature (LCST) of a watersoluble polymer that has an LCST of from about 7° C. to about 70° C. inwater, wherein the polymer is made from a ratio m/n of (m hydrophilicorganic groups)/(n hydrophobic organic groups), connected via organiclinking groups, the method comprising: controlling the LCST temperaturesensitivity by varying the m/n ratio, while maintaining the polymermicrostructure of a linear chain and avoiding clustering inhydrophilic-only or hydrophobic-only sequences with more than 30homologous (hydrophilic or hydrophobic) groups in each sequence.
 11. Themethod of claim 10 comprising controlling the LCST temperaturesensitivity by varying the m/n ratio, while avoiding clustering inhydrophilic-only or hydrophobic-only sequences with more than 30homologous (hydrophilic or hydrophobic) groups in each sequence andmaintaining a mostly linear polymer microstructure with short branches,wherein the branches are not hydrophilic-only or hydrophobic-onlysequences and the polymer backbone is not a hydrophilic-only orhydrophobic-only sequence.
 12. The temperature sensitive polymer ofclaim 3, wherein the hydrophilic and hydrophobic groups alternate.